Chemical Susceptibility, Injury and Reactivity: Mechanisms and

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Measurement with emphasis on developmental and receptor-

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ligand considerations

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S.C. Rowat

2001

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Brief Table of Contents

Full Table of Contents .iv

Abstract.. vi

Abbreviations Usedvii

1. Introduction and Overview of CSIR 1

1A. Context and Aims .1

1B. Overview Hypothesis: Susceptibility, Injury, and Reactivity .1

1C. Formulating CSIR Mechanism Models .2

2. Specific CSIR Mechanisms: Newer Candidates ..4

2A. Genetic Variation in Xenobiotic Metabolizing Enzymes (XMEs) ..4

2B. Modulation of Receptor-Ligand Systems .5

2C. Early Developmental Windows .11

2D. Chronic Modulators as CSIR Mechanisms..22

2E. Combined and Synergistic Mechanisms 35

3. CSIR Measurement: what, how, and examples 37

3A. Symptoms: Static, Cyclic, and Triggered .37

3B. Instruments: Machine, Patient, and Clinician .37

3C. Complexity of Individual CSIR Study Designs .39

3D. CSIR Measurement Discussion and Postulates .44

4. Final Discussion: Theories and Implications..48

4A. Function Switching Further Explored 48

4B. Is the Receptor-ligand Web a Form of Factor Analysis?..49

4C. Chemical Reactivity as Complex Phenomena 51

4D. Implications For Chemical Study and Control ..53

5. Summary .57

6. Final Conclusions.60

7. Appendix: OP Study Summaries ..61

7A. OP Animal Studies61

7B. Human OP Studies 62

8. References65